Detecting the Native Ligand Orientation by Interfacial Rigidity

"A novel approach to pose selection in protein-ligand docking based on graph theory" presented at the Departmental Retreat at Michigan State University on October 7, 2016

Transcript

1. Biochemistry & Molecular Biology ! Departmental Retreat October 7, 2016; Okemos Conference Center ! Sebastian Raschka Leslie A. Kuhn Lab Detecting the Native Ligand Orientation by Interfacial Rigidity
2. Binding Mode Prediction Crystal structure of the complex between carboxypeptidase A and the biproduct analog inhibitor L-benzylsuccinate (PDB code: 1cbx)
3. near-native binding mode → rigid binding pocket “bad” docking → flexible binding pocket Hypothesis
4. Chorismate mutase and prephenate (PDB code: 1com) ProFlex: D. J. Jacobs, A. J. Rader, L. A. Kuhn, and M. F. Thorpe (2001) Protein Flexibility Predictions Using Graph Theory. Proteins: 44, 150-165 . near-native binding mode → rigid binding pocket “bad” docking → flexible binding pocket
5. APO HOLO
6. 2.8 Å RMSD 1.0 Å RMSD Crystal Pose Crystal structure of the complex between carboxypeptidase A and the biproduct analog inhibitor L-benzylsuccinate (PDB code: 1cbx)
7. Ligand Pose RMSD (Å) Number of Complexes
8. Ligand Pose RMSD (Å) Number of Complexes
9. Ligand Pose RMSD (Å) Number of Complexes
10. APO SET Number of Complexes Ligand Pose RMSD (Å)
11. 3.  New information / signal (cooperativity) 1.  Competitive scoring function for binding mode prediction / docking 2.  Robust, no “bad” predictions
12. http://www.kuhnlab.bmb.msu.edu/software https://psa-lab.github.io/siteinter lock ite nterlock S I R a s c h k a , Bemister- Buf fi ng ton , an d Ku hn 2 0 1 6 . P r o t e i n s . D O I : 1 0 . 1 0 0 2 / p r o t . 2 5 1 7 2. (In press.)
13. PROTEIN STRUCTURE AND ANALYSIS LAB Dr. Leslie Kuhn (Lab. Director) Joseph Bemister-Buffington (Undergrad. Researcher) Alex Wolf (Undergrad. Researcher) http://www.kuhnlab.bmb.msu.edu
14. THANK YOU
16. Chao-Yie Yang R, Wang A, Wang S. A Systematic analysis of the effect of small-molecule binding on protein flexibility of the ligand- binding sites. J Med Chem 2005;5648–5650.